CLL is an incurable disease characterized by the clonal proliferation and accumulation of neoplastic B lymphocytes. Patients with advanced stage disease or those who progress to the state of requiring treatment have a median survival of only 18 to 36 months, indicating a clear need for the evaluation of new therapeutic candidates. Fludarabine is a standard first line treatment, but treatment failures remain a challenging problem. The monoclonal antibody alemtuzmab is approved for CLL but shows a significant incidence of infections due to T-cell suppression. The monoclonal antibody rituximab has also been shown to be beneficial, especially in comparison with fludarabine, but with reduced toxicity compared to alemtuzumab. A Phase 2 trial will be carried out to assess the efficacy of the combination of a novel anticancer agent, tablostat(PT-100) and rituximab (anti-CD20 monoclonal antibody) in patients with advanced CLL who failed to respond, or have progressed following a prior response, to a FR-containing regimen. Tablostat is an orally available synthetic dipeptide that has shown potent anti-cancer and hematopoietic activities in mice relating to the upregulation of cytokines and chemokines. Up to 54 patients will be treated for 28 days (4 treatment cycles each for rituximab and tablostat), then followed for 12 months. The primary efficacy measure is overall response rate (partial and complete response), with secondary endpoints of complete response, progression-free survival, duration of response and survival. Tablostat should enhance the effectiveness of rituximab via upregulation of innate immune responses, and provide independent anti-cancer effects. Mouse studies with talabostat alone and in combination with rituximab provide experimental support for this hypothesis. Positive results will be critical to support continued development and ultimately the approval of talabostat as a CLL therapy.